Metoprolol succinate

Description

Metoprolol succinate is a beta1-selective (cardioselective) adrenoceptor blocking agent intended for oral administration, available as extended-release tablets. These tablets are formulated to provide a controlled and predictable release of metoprolol, allowing for once-daily dosing. Each tablet contains metoprolol succinate in a multiple unit system comprising numerous controlled release pellets, with each pellet functioning as an independent drug delivery unit designed to release metoprolol continuously throughout the dosage interval.

The tablets are available in strengths of 47.5 mg, 95 mg, and 190 mg of metoprolol succinate, which are equivalent to 50 mg, 100 mg, and 200 mg of metoprolol tartrate, respectively. The chemical name of metoprolol succinate is (±) 1(isopropylamino)-3-p-(2-methoxyethyl) phenoxy-2-propanol succinate (2:1) (salt), and its structural formula is represented accordingly. Metoprolol succinate, USP is a white crystalline powder with a molecular weight of 652.8, exhibiting high solubility in water and solubility in methanol.

Inactive ingredients in the formulation include acetyl tributyl citrate, colloidal silicon dioxide, crosspovidone, ethyl cellulose, hydroxypropyl cellulose, hypromellose, isopropyl alcohol, methylene chloride, microcrystalline cellulose, microcrystalline cellulose sphere, polyethylene glycol, sodium stearyl fumarate, and talc. The tablets are film-coated with Opadry white 04F58804, which contains hypromellose, polyethylene glycol, and titanium dioxide.

Uses and Indications

Metoprolol succinate extended-release tablets are indicated for the treatment of hypertension, angina pectoris, and heart failure.

This drug is indicated for hypertension to lower blood pressure, thereby reducing the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. It is also indicated for the management of angina pectoris. In patients with heart failure, metoprolol succinate extended-release tablets are indicated to reduce the risk of cardiovascular mortality and hospitalizations due to heart failure.

There are no teratogenic or nonteratogenic effects associated with this medication.

Dosage and Administration

The medication is to be administered once daily. Dosing should be titrated at weekly or longer intervals as needed and tolerated.

For the management of hypertension, the starting dose is between 25 mg and 100 mg. In cases of angina pectoris, the recommended starting dose is 100 mg. For heart failure, the initial dose may be either 12.5 mg or 25 mg, depending on the patient's condition and response.

When transitioning from immediate-release metoprolol to metoprolol succinate extended-release tablets, it is essential to maintain the same total daily dose of metoprolol succinate extended-release tablets as the patient was receiving with the immediate-release formulation.

Contraindications

Use of this product is contraindicated in patients with known hypersensitivity to any of its components.

Additionally, it should not be administered to individuals with severe bradycardia, including those with greater than first-degree heart block or sick sinus syndrome who do not have a pacemaker.

The product is also contraindicated in cases of cardiogenic shock or decompensated heart failure, as these conditions may exacerbate the risks associated with its use.

Warnings and Precautions

Abrupt cessation of beta-blocker therapy may lead to exacerbation of myocardial ischemia. Therefore, it is crucial to taper the dosage gradually under medical supervision to mitigate this risk.

In patients with heart failure, there is a potential for worsening cardiac function. Continuous monitoring of cardiac status is recommended to ensure that any deterioration is promptly addressed.

For individuals with bronchospastic disease, the use of beta-blockers is contraindicated due to the risk of bronchospasm. Healthcare professionals should consider alternative therapies for these patients.

Concomitant administration of beta-blockers with glycosides, clonidine, diltiazem, or verapamil may increase the likelihood of bradycardia. Close monitoring of heart rate and rhythm is advised when these medications are used together.

In cases of pheochromocytoma, it is essential to initiate therapy with an alpha-blocker prior to starting beta-blocker treatment to prevent hypertensive crises.

During major surgical procedures, particularly non-cardiac surgeries, the initiation of high-dose extended-release metoprolol should be avoided. Additionally, chronic beta-blocker therapy should not be routinely withdrawn before surgery, as this may lead to adverse cardiovascular events.

Patients on beta-blockers may experience an increased risk of hypoglycemia, and these medications can mask the early warning signs of low blood sugar. Regular monitoring of blood glucose levels is recommended, especially in diabetic patients.

In patients with thyrotoxicosis, abrupt withdrawal of beta-blockers can precipitate a thyroid storm, a life-threatening condition. Therefore, careful management and gradual dose adjustments are necessary in this population.

For individuals with peripheral vascular disease, beta-blockers may exacerbate symptoms of arterial insufficiency. Monitoring of peripheral circulation is advised to assess for any worsening of symptoms.

Lastly, patients receiving beta-blockers may exhibit reduced responsiveness to the standard doses of epinephrine used in the treatment of allergic reactions. Healthcare providers should be aware of this potential interaction and consider alternative dosing strategies in emergency situations.

Side Effects

Patients receiving treatment may experience a range of adverse reactions. The most common adverse reactions reported include tiredness, dizziness, depression, shortness of breath, bradycardia, hypotension, diarrhea, pruritus, and rash.

Serious adverse reactions have also been observed. Worsening cardiac failure may occur in patients with pre-existing heart conditions. Abrupt cessation of therapy can exacerbate myocardial ischemia, and patients with bronchospastic disease should avoid beta blockers due to the risk of bronchospasm. Additionally, the concomitant use of glycosides, clonidine, diltiazem, and verapamil with beta-blockers may increase the risk of bradycardia.

In patients with pheochromocytoma, it is recommended to initiate therapy with an alpha-blocker. During major surgery, the initiation of high-dose extended-release metoprolol should be avoided in patients undergoing non-cardiac procedures, and chronic beta-blocker therapy should not routinely be withdrawn prior to surgery.

Patients may also be at increased risk for hypoglycemia, which can mask early warning signs of low blood sugar. In those with thyrotoxicosis, abrupt withdrawal of treatment may precipitate a thyroid storm. Furthermore, patients with peripheral vascular disease may experience aggravated symptoms of arterial insufficiency. It is important to note that patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

In cases of overdosage, patients may present with severe bradycardia, hypotension, and cardiogenic shock. Other clinical manifestations can include atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, as well as nausea and vomiting.

Contraindications for treatment include known hypersensitivity to the product components, severe bradycardia (greater than first-degree heart block), sick sinus syndrome without a pacemaker, and cardiogenic shock or decompensated heart failure.

Drug Interactions

Catecholamine-depleting drugs, when administered concurrently with beta-blocking agents, may produce an additive effect. This interaction necessitates careful monitoring of blood pressure and heart rate, as the combined effects could lead to significant cardiovascular changes.

Inhibitors of the CYP2D6 enzyme are known to increase the concentration of metoprolol. Clinicians should consider dosage adjustments of metoprolol when prescribing CYP2D6 inhibitors to mitigate the risk of adverse effects associated with elevated drug levels.

Additionally, beta-blockers, including metoprolol, may worsen rebound hypertension following the discontinuation of clonidine. It is advisable to monitor patients closely for signs of increased blood pressure during the withdrawal period of clonidine, particularly in those who are also receiving beta-blocker therapy.

Packaging & NDC

The table below lists all NDC Code configurations of Metoprolol Succinate, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

One hundred forty-four hypertensive pediatric patients aged 6 to 16 years were randomized to receive either placebo or one of three dose levels of metoprolol succinate extended-release tablets (0.2, 1, or 2 mg/kg once daily) for a duration of 4 weeks. The safety and effectiveness of metoprolol succinate extended-release tablets have not been established in patients younger than 6 years of age.

Geriatric Use

Clinical studies of metoprolol succinate extended-release tablets in the treatment of hypertension did not include a sufficient number of subjects aged 65 and older to determine whether these elderly patients respond differently compared to younger individuals. However, other clinical experiences in hypertensive patients have not identified any significant differences in responses between elderly and younger patients.

In the MERIT-HF trial, which involved 1,990 patients with heart failure randomized to metoprolol succinate extended-release tablets, 50% of the participants were aged 65 years and older, and 12% were aged 75 years and older. The findings from this trial indicated no notable differences in efficacy or the rate of adverse reactions between older and younger patients.

Given the greater frequency of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies in geriatric patients, it is generally recommended to initiate treatment with a low starting dose in this population. Careful monitoring is advised to ensure safety and efficacy in elderly patients receiving metoprolol succinate extended-release tablets.

Pregnancy

Untreated hypertension and heart failure during pregnancy can lead to adverse outcomes for both the mother and the fetus. Available data from published observational studies have not demonstrated a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes with the use of metoprolol during pregnancy. However, there are inconsistent reports regarding intrauterine growth restriction, preterm birth, and perinatal mortality associated with maternal use of beta-blockers, including metoprolol, during pregnancy.

In animal reproduction studies, metoprolol has been shown to increase post-implantation loss and decrease neonatal survival in rats at oral dosages of 500 mg/kg/day, which is approximately 24 times the daily dose of 200 mg in a 60-kg patient on a mg/m² basis. No fetal abnormalities were observed when pregnant rats received metoprolol orally at doses up to 200 mg/kg/day, which is 10 times the daily dose of 200 mg in a 60-kg patient. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown; however, all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications, while also increasing the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Additionally, stroke volume and heart rate increase during pregnancy, leading to increased cardiac output, particularly during the first trimester. There is also a risk for preterm birth in pregnant women with chronic heart failure during the third trimester.

Metoprolol crosses the placenta, and neonates born to mothers receiving metoprolol during pregnancy may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. It is recommended to observe neonates and manage them accordingly. While data from published observational studies did not demonstrate an association of major congenital malformations with the use of metoprolol in pregnancy, the findings regarding intrauterine growth retardation, preterm birth, and perinatal mortality are inconsistent and may be influenced by methodological limitations, including retrospective design, concomitant use of other medications, and unadjusted confounders related to the underlying disease in the mother. These observational studies cannot definitively establish or exclude any drug-associated risk during pregnancy.

Lactation

There is no specific information available regarding the use of this medication in nursing mothers or its effects on lactation. Consequently, the potential for excretion in breast milk and the impact on breastfed infants remain undetermined. Healthcare professionals should exercise caution and consider the lack of data when advising lactating mothers on the use of this medication.

Renal Impairment

Patients with renal impairment have no specific information regarding dosage adjustments, special monitoring, or safety considerations provided in the text. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing to this population. Regular monitoring of renal function may be warranted in patients with reduced kidney function to ensure safety and efficacy.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Overdosage of metoprolol succinate can result in a range of severe clinical manifestations. The most notable signs and symptoms include severe bradycardia, hypotension, and cardiogenic shock. Additionally, patients may present with atrioventricular block, heart failure, bronchospasm, hypoxia, and varying levels of consciousness, including coma. Gastrointestinal symptoms such as nausea and vomiting may also occur.

In the event of an overdose, it is crucial to consider intensive care management, particularly for patients with underlying conditions such as myocardial infarction or heart failure, as they may experience significant hemodynamic instability. It is important to note that beta-blocker overdose can lead to considerable resistance to resuscitation efforts with adrenergic agents, including beta-agonists.

Management strategies should be tailored based on the pharmacologic actions of metoprolol. Hemodialysis is generally not effective for the elimination of metoprolol from the body.

For bradycardia, healthcare professionals should assess the necessity of administering atropine, adrenergic-stimulating drugs, or the placement of a pacemaker to address bradycardia and conduction disorders. In cases of hypotension, it is essential to treat the underlying bradycardia and consider the use of intravenous vasopressor infusions, such as dopamine or norepinephrine.

Heart failure and shock may require appropriate interventions, including volume expansion and the administration of glucagon, which may be followed by an intravenous infusion of glucagon if necessary. Additionally, intravenous adrenergic drugs such as dobutamine may be indicated, with α1 receptor agonists considered in the presence of vasodilation.

Bronchospasm associated with overdose can typically be managed with bronchodilators, which are effective in reversing this condition.

Nonclinical Toxicology

Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In 2-year studies in rats at three oral dosage levels of up to 800 mg/kg/day (41 times, on a mg/m² basis, the daily dose of 200 mg for a 60-kg patient), there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug-related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia.

In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg/day (18 times, on a mg/m² basis, the daily dose of 200 mg for a 60-kg patient), benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. However, there was no increase in malignant or total (benign plus malignant) lung tumors, nor in the overall incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor.

All genotoxicity tests performed on metoprolol tartrate, including a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei, were negative. Similarly, metoprolol succinate was also tested in a Salmonella/mammalian-microsome mutagenicity test with negative results.

No evidence of impaired fertility due to metoprolol tartrate was observed in a study performed in rats at doses up to 22 times, on a mg/m² basis, the daily dose of 200 mg in a 60-kg patient.

Postmarketing Experience

Postmarketing experience has identified several adverse reactions associated with metoprolol succinate extended-release tablets. These include bradycardia, heart block, hypotension, dizziness, fatigue, depression, shortness of breath, peripheral edema, weight gain, and hypoglycemia.

Additionally, there have been reports of anaphylactic reactions, angioedema, hepatic dysfunction, and exacerbation of psoriasis.

Cases of withdrawal symptoms following abrupt discontinuation of the medication have also been documented, including palpitations, tachycardia, hypertension, and myocardial infarction.

The safety profile of metoprolol succinate extended-release tablets continues to be monitored through ongoing postmarketing surveillance.

Patient Counseling

Patients should be advised to take metoprolol succinate extended-release tablets regularly and continuously, as directed, preferably with or immediately following meals. In the event that a dose is missed, patients should take only the next scheduled dose and should not double the dose. It is important for patients to understand that they should not interrupt or discontinue the use of metoprolol succinate extended-release tablets without first consulting their physician.

Healthcare providers should inform patients to avoid operating automobiles and machinery or engaging in other tasks that require alertness until their response to therapy with metoprolol succinate extended-release tablets has been determined. Patients should be instructed to contact their physician if they experience any difficulty in breathing. Additionally, patients should inform their physician or dentist prior to any type of surgery that they are taking metoprolol succinate extended-release tablets.

For patients with heart failure, it is crucial to advise them to consult their physician if they notice any signs or symptoms of worsening heart failure, such as weight gain or increasing shortness of breath. Patients or caregivers should also be informed about the risk of hypoglycemia when metoprolol succinate extended-release tablets are administered to patients who are fasting or experiencing vomiting. It is essential to instruct patients or caregivers on how to monitor for signs of hypoglycemia effectively.

Storage and Handling

The product is supplied in a tight container, in accordance with USP standards. It should be stored at a temperature of 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F). Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Metoprolol Succinate as submitted by BluePoint Laboratories. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)